To the Editor:

A common variant (rs738409 C>G) in the PNPLA3 gene has been consistently associated with liver fat but also fibrosis in nonalcoholic fatty liver disease, alcoholic liver disease (ALD), and chronic hepatitis C (CHC).1-4 The study by Valenti et al.4 in a recent issue of HEPATOLOGY shows that in Caucasian CHC patients, this variant was also linked to hepatocellular carcinoma (HCC). This latter finding has been replicated in another independent European cohort.5

We tested the association between rs738409 and HCC in ALD. To this end, we genotyped 325 Caucasian patients from Belgium with alcoholic cirrhosis (67% men; mean age, 54.9 ± 9.1 years; mean body mass index [BMI], 26.7±5.5 kg/m2; 17% had diabetes) and 246 French Caucasian patients with alcoholic cirrhosis (86% men; mean age, 64.3±9.1 years; mean BMI, 27.4±4.9 kg/m2; 37% had diabetes). HCC was confirmed by histology or typical imaging findings in 12% of the Belgian cohort and 43% of the French cohort. The French unit included a higher proportion of HCC patients, reflecting the specificity of this tertiary center specializing in liver cancer management. HCC was present in 9% of CC, 10% of CG, and 25% of GG genotype in the Belgian cohort and in 28% of CC, 41% of CG, and 78% of GG genotype in the French group. The minor allele frequency was not statistically different between the Belgian and French centers (36.8% versus 39.8% [P = 0.296]). Under a recessive model of inheritance, rs738409 was significantly associated with HCC after adjustment for, age, sex, BMI, and diabetes in both cohorts (Table 1).

Table 1. Multivariable Logistic Regression Analysis for the Association of PNPLA3 (rs738409 C>G) Variant and HCC
 Belgian Cohort (n = 325)French Cohort (n = 246)Overall (n = 571)
OR (95% CI)POR (95% CI)POR (95% CI)P
  • Abbreviations: HCC, hepatocellular carcinoma; BMI, body mass index; CI, confidence interval; OR, odds ratio.

  • *

    Based on a recessive model for rs738409 genotype.

rs738409 GG*3.17 (1.39-7.21)0.0069.23 (3.37-25.27)1.50 × 10−54.70 (2.63-8.42)1.83 × 10−7
Age, years1.04 (0.99-1.08)0.1071.09 (1.05-1.13)2.00 × 10−51.08 (1.06-1.11)5.36 × 10−10
Sex, men1.15 (0.53-2.51)0.72814.03 (2.94-66.90)0.0013.17 (1.64-6.13)0.001
BMI (kg/m2)1.05 (0.98-1.12)0.1501.03 (0.97-1.11)0.3491.04 (0.99-1.08)0.146
Diabetes2.30 (1.05-5.04)0.0381.39 (0.73-2.65)0.3221.89 (1.17-3.04)0.009

The rs738409 variant is associated with liver fat accumulation; however, the exact function of PNPLA3 and the consequence of the related nonsynonymous variation remains unknown.6 Although the remarkable observation that rs738409 confers higher risk of HCC in CHC and ALD warrants additional replication, it may well illustrate gene-host interactions and indicate that the influence of PNPLA3 on chronic liver disease heritability could go far beyond a mere impact on steatosis.


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  • 1
    Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. HEPATOLOGY 2011; 53: 1883-1894.
  • 2
    Stickel F, Buch S, Lau K, zu Schwabedissen HM, Berg T, Ridinger M, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. HEPATOLOGY 2011; 53: 86-95.
  • 3
    Trépo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T, et al. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. HEPATOLOGY 2011; 54: 60-69.
  • 4
    Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, et al. Patatin-Like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. HEPATOLOGY 2011; 53: 791-799.
  • 5
    Corradini SG, Burza MA, Molinaro A, Romeo S. Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma. HEPATOLOGY 2011; 53: 1776.
  • 6
    Browning JD, Cohen JC, Hobbs HH. Patatin-like phospholipase domain-containing 3 and the pathogenesis and progression of pediatric nonalcoholic fatty liver disease. HEPATOLOGY 2010; 52: 1189-1192.

Eric Trépo* †, Erwan Guyot‡ §, Nathalie Ganne-Carrié¶, Delphine Degré* †, Thierry Gustot* †, Denis Franchimont* †, Angela Sutton‡ §, Pierre Nahon¶ **, Christophe Moreno M.D., Ph.D.* †, * Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Erasme Hospital, † Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium, ‡ INSERM U6988, Université Paris 13, Bobigny, France, § Service de Biochimie, Hŏpital Jean Verdier, AP-HP, Bondy, France, ¶ Service d'Hépatologie, Hŏpital Jean Verdier, AP-HP, Bondy, France, ** INSERM U773, Centre de Recherche Bichat Beaujon CRB3, Université Paris 7, Paris, France.